Celeste Beck1, Amanda Allshouse2, Robert M Silver3, William A Grobman4, Hyagriv Simhan5, David Haas6, Uma M Reddy7, Nathan R Blue3. 1. Department of Nutritional Sciences, Pennsylvania State University, State College, PA (Ms Beck). Electronic address: beckceleste@gmail.com. 2. Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, UT (Ms Allshouse and Drs Silver and Blue). 3. Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, UT (Ms Allshouse and Drs Silver and Blue); Department of Maternal-Fetal Medicine, Intermountain Healthcare, Salt Lake City, UT (Drs Silver and Blue). 4. Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL (Dr Grobman). 5. Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA (Dr Simhan). 6. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN (Dr Haas). 7. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University, New Haven, CT (Dr Reddy).
Abstract
BACKGROUND: Obesity is associated with various placenta-mediated adverse pregnancy outcomes, including preeclampsia, preterm birth, and stillbirth. Mechanisms linking obesity with placental dysfunction are not completely understood. OBJECTIVE: This study aimed to examine the relationship between early pregnancy body mass index and placental angiogenic biomarkers soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio. STUDY DESIGN: We conducted secondary analyses of an existing substudy within a multisite, prospective observational cohort study of nulliparous pregnant women in the United States. First- and second-trimester maternal blood samples, first-trimester body mass index, and demographic, lifestyle, and pregnancy outcomes data were collected. Soluble fms-like tyrosine kinase-1 and placental growth factor concentrations were measured at 6 to 13 and 16 to 22 weeks of gestation for women (cases) who experienced one of several adverse pregnancy outcomes (delivery at <37 weeks of gestation, preeclampsia or eclampsia, birthweight for gestational age <5th percentile, or stillbirth) and for those who had none of those outcomes (controls). We used multivariable mixed-effects linear regression models to estimate the association of body mass index with angiogenic biomarkers at both time points. We evaluated mean change between first- and second-trimester biomarker concentrations using multivariable linear regression models. Lastly, we used logistic regression models to estimate the risk of a high second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratio, using clinically established cutoffs for risk prediction. RESULTS: Angiogenic biomarker and early pregnancy body mass index data were available for 2363 women (1467 with adverse pregnancy outcomes and 896 controls). High early pregnancy body mass index was associated with consistently lower soluble fms-like tyrosine kinase-1 concentrations across the first and second trimesters of pregnancy. We found lower first-trimester placental growth factor concentrations in the group with class II or III obesity (P<.001) and lower second-trimester placental growth factor concentrations among groups who were overweight, with class I obesity, and class II or III obesity (P<.001). For every unit increase in early pregnancy body mass index, there was a -4.4 pg/mL (95% confidence interval, -3.6 to -5.2) smaller mean increase in placental growth factor concentrations between the first and second trimesters of pregnancy. These differences resulted in significantly lower mean first-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratios among groups who were overweight, with class I obesity, and class II or III obesity (P<.05) and in a significantly higher second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratio among the group with class II or III obesity (P<.001), compared with the group with normal body mass index. Each unit of increase in body mass index was associated with a 0.5 (95% confidence interval, 0.3-0.7) greater mean increase in the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio between the first and second trimesters of pregnancy. In stratified analyses, associations between body mass index and angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were similar in nonadverse pregnancy outcome and adverse pregnancy outcome subgroups, whereas associations between body mass index and the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio were attenuated in the subgroups. Participants in the group with class II or III obesity were 3.13 (95% confidence interval, 1.15-8.49) times more likely than participants with normal weight to have a second-trimester ratio of ≥38 in univariate analysis. CONCLUSION: High early pregnancy body mass index was associated with lower soluble fms-like tyrosine kinase-1 and placental growth factor concentrations across early pregnancy. Maternal body mass was inversely associated with first-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratios and positively associated with second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratios, driven by a diminished rise in placental growth factor between the first and second trimesters of pregnancy. Women with class II or III obesity have an increased risk of a high second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratio associated with placental dysfunction.
BACKGROUND: Obesity is associated with various placenta-mediated adverse pregnancy outcomes, including preeclampsia, preterm birth, and stillbirth. Mechanisms linking obesity with placental dysfunction are not completely understood. OBJECTIVE: This study aimed to examine the relationship between early pregnancy body mass index and placental angiogenic biomarkers soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio. STUDY DESIGN: We conducted secondary analyses of an existing substudy within a multisite, prospective observational cohort study of nulliparous pregnant women in the United States. First- and second-trimester maternal blood samples, first-trimester body mass index, and demographic, lifestyle, and pregnancy outcomes data were collected. Soluble fms-like tyrosine kinase-1 and placental growth factor concentrations were measured at 6 to 13 and 16 to 22 weeks of gestation for women (cases) who experienced one of several adverse pregnancy outcomes (delivery at <37 weeks of gestation, preeclampsia or eclampsia, birthweight for gestational age <5th percentile, or stillbirth) and for those who had none of those outcomes (controls). We used multivariable mixed-effects linear regression models to estimate the association of body mass index with angiogenic biomarkers at both time points. We evaluated mean change between first- and second-trimester biomarker concentrations using multivariable linear regression models. Lastly, we used logistic regression models to estimate the risk of a high second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratio, using clinically established cutoffs for risk prediction. RESULTS: Angiogenic biomarker and early pregnancy body mass index data were available for 2363 women (1467 with adverse pregnancy outcomes and 896 controls). High early pregnancy body mass index was associated with consistently lower soluble fms-like tyrosine kinase-1 concentrations across the first and second trimesters of pregnancy. We found lower first-trimester placental growth factor concentrations in the group with class II or III obesity (P<.001) and lower second-trimester placental growth factor concentrations among groups who were overweight, with class I obesity, and class II or III obesity (P<.001). For every unit increase in early pregnancy body mass index, there was a -4.4 pg/mL (95% confidence interval, -3.6 to -5.2) smaller mean increase in placental growth factor concentrations between the first and second trimesters of pregnancy. These differences resulted in significantly lower mean first-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratios among groups who were overweight, with class I obesity, and class II or III obesity (P<.05) and in a significantly higher second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratio among the group with class II or III obesity (P<.001), compared with the group with normal body mass index. Each unit of increase in body mass index was associated with a 0.5 (95% confidence interval, 0.3-0.7) greater mean increase in the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio between the first and second trimesters of pregnancy. In stratified analyses, associations between body mass index and angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were similar in nonadverse pregnancy outcome and adverse pregnancy outcome subgroups, whereas associations between body mass index and the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio were attenuated in the subgroups. Participants in the group with class II or III obesity were 3.13 (95% confidence interval, 1.15-8.49) times more likely than participants with normal weight to have a second-trimester ratio of ≥38 in univariate analysis. CONCLUSION: High early pregnancy body mass index was associated with lower soluble fms-like tyrosine kinase-1 and placental growth factor concentrations across early pregnancy. Maternal body mass was inversely associated with first-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratios and positively associated with second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratios, driven by a diminished rise in placental growth factor between the first and second trimesters of pregnancy. Women with class II or III obesity have an increased risk of a high second-trimester soluble fms-like tyrosine kinase-1-to-placental growth factor ratio associated with placental dysfunction.
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